Cyclic adhesion inhibitors

ABSTRACT

The invention concerns cyclopeptides of formula (I): Cyclo-(Arg-Gly-Asp-X-Y) in which X is Cha, Nal, Phe, 2-R 1  -Phe, 3-R 1  -Phe, 4-R 1  -Phe, homo-Phe, Phg, Thi, Trp, Tyr or derivatives of Tyr, whereby the OH group can be etherified by alkyl groups containing 1-18 C-atoms and the amino-acid groups given can also be derivatives, R 1  is NH 2 , NO 2 , I Br, Cl, F, alkyl with 1-18 C-atoms, Ar, Ar--O or 3  H, Y is Gly in which the α N-atom may be substituted by R 2  and/or the α C-atom may be substituted by R 3  and/or R 4 , with the provision that Gly has at least one of the substituents specified, Ar is phenyl which may be substituted by one or two of groups NH 2 , NO 2 , I, Br, Cl, F, alkyl with 1-6 C-atoms or  3  H, R 2 , R 3  or R 4 , independently of each other, are alkyl with 1-18 C-atoms or R 2  and R 3  or R 3  and R 4  together in each case are a branched or unbranched alklyene chain with 3 to 18 C-atoms so that either the α N-atom or the α C-atom together with the alkylene chain, or the α C-atom alone, forms a ring with alkylene chain, whereby, when optically active amino-acid or amino-acid-derivative groups are involved, both the D- and the L-form are included, plus derivatives, in particular the β-ester of aspartic acid or N-guanidine acyl derivatives of arginine or prodrug as well as their physiologically acceptable salts. These compounds act as integrin inhibitors and may be used particularly for the prophylaxis and treatment of circulatory and angiogenic conditions and microbial infections as well as in tumor therapy.

The invention relates to novel cyclopeptides of the formula I

    cyclo-(Arg-Gly-Asp-X-Y)                                    I,

in which

X is Cha, Nal, Phe, 2-R¹ -Phe, 3-R¹ -Phe, 4-R¹ -Phe, homo-Phe, Phg, Thi,Trp, Tyr or derivatives of Tyr, it being possible for the OH group to beetherified by alkyl radicals having 1-18 carbon atoms and also for theamino acid residues mentioned to be additionally derivatized,

R¹ is NH₂, NO₂, I, Br, Cl, F, alkyl having 1-18 carbon atoms, Ar, Ar--Oor ³ H,

Y is Gly, it being possible for the α N atom to be substituted by R²and/or the α C atom to be substituted by R³ and/or R⁴, with the provisothat Gly is substituted at least once in the manner indicated,

Ar is phenyl which can optionally be substituted once or twice by NH₂,NO₂, I, Br, Cl, F, alkyl having 1-6 carbon atoms or ³ H,

R², R³, or R⁴ are each independently of one another alkyl having 1-18carbon atoms,

or else

R₂ and R₃ or R³ and R⁴ in each case together are otherwise a branched orunbranched alkylene chain having 3 to 18 carbon atoms, so that thereineither the α N atom and the α C atom together with the alkylene chain,or the α C atom alone with the alkylene chain, forms a ring,

and, where residues of optically active amino acids and amino acidderivatives are involved, both the D and the L forms are included, andto derivatives, especially aspartic acid β-esters or N-guanidine-acylderivatives of arginine, to prodrugs, and also to the physiologicallyacceptable salts thereof.

Similar compounds are known from, for example, EP 0 406 428 and FEBSLett. 291, 50-54 (1991).

The object of the invention was to discover novel compounds havingvaluable properties, especially those which can be used for theproduction of medicaments.

It has surprisingly been found that the compounds of the formula I andtheir salts possess very valuable properties. In particular, they act asintegrin inhibitors, in which context they inhibit in particular theinteractions of β₃ - or β₅ -integrin receptors with ligands. Thecompounds are particularly active in the case of the integrins a_(V) β₃,a_(V) β₅ and a_(II) β₃, but also relative to a_(V) β₁ -, a_(V) β₆ - anda_(V) β₈ receptors. These actions can be demonstrated, for example,according to the method described by J. W. Smith et al. in J. Biol.Chem. 265, 12267-12271 (1990). In addition, there are anti-inflammatoryeffects.

The dependency of the development of angiogenesis on the interactionbetween vascular integrins and extra-cellular matrix proteins isdescribed by P. C. Brooks, R. A. Clark and D. A. Cheresh in Science 264,569-71 (1994).

The possibility of inhibiting this interaction and the associatedinitiation of apotosis (programmed cell death) of angiogenic vascularcells by a cyclic peptide is described by P. C. Brooks, A. M.Montgomery, M. Rosenfeld, R. A. Reisfeld, T.-Hu, G. Klier and D. A.Cheresh in Cell 79, 1157-64 (1994).

Compounds of the formula I which block the interaction of integrinreceptors and ligands, for example of fibrinogen to the fibrinogenreceptor (glycoprotein IIb/IIIa), act as GPIIb/IIIa antagonists inpreventing the propagation of tumour cells by metastasis. This isdemonstrated by the following observations:

The propagation of tumour cells from a local tumour into the vascularsystem takes place via the formation of microaggregates (microthrombi)by interaction of the tumour cells with blood platelets. The tumourcells are screened by the protection afforded in the microaggregates,and are not recognized by the cells of the immune system.

The microaggregates are able to settle on vessel walls, facilitating thefurther penetration of tumour cells into the tissue. Since the formationof the microthrombi is mediated by binding of fibrinogen to thefibrinogen receptors on activated blood platelets, the GPIIa/IIIbantagonists can be regarded as effective inhibitors of metastasis.

The compounds of the formula I can also be employed as antimicrobialsubstances in the case of operations where biomaterials, implants,catheters or pacemakers are employed. In this context they have anantiseptic action. The effectiveness of the antimicrobial activity canbe demonstrated by the method described by P. Valentin-Weigund et al.,in Infection and Immunity, 2851-2855 (1988).

Since the compounds of the formula I constitute inhibitors of fibrinogenbinding and thus ligands of the fibrinogen receptors on blood platelets,they can be used in vivo in the vascular system as diagnostic agents forthe detection and location of thrombi, provided that they aresubstituted, for example, by a radioactive or UV-detectable radical.

The compounds of the formula I, as inhibitors of fibrinogen binding, canalso be used as effective aids in studying the metabolism of bloodplatelets in different activation stages or of intracellular signalmechanisms of the fibrinogen receptor. The detectable unit of anincorporated label, for example isotope labelling by means of ³ H, afterbinding to the receptor, enables the said mechanisms to be investigated.

The compounds therefore have the property of inhibiting the binding ofnatural or synthetic ligands to integrins, especially the integrinsα_(V) β₃, α_(V) β₅ and α_(IIb) β₃, but also of α_(V) β₁, α_(V) β₆ andα_(V) β₈.

Moreover, they have the advantage over the prior art that α-N-alkylationor α-C-alkylation of the Y-amino acid brings about metabolicstabilization and increased fat-solubility. Through the reduction inpossible hydrogen bridges, since N-alkyl, for example, cannot be an Hdonor for C═O, the capacity to penetrate membranes is improved, so thatit is possible to obtain increased oral absorbability; moreover,increased plasma protein binding may occur.

The α-N-alkylation or α-C-alkylation of the Y-amino acid unit increasesthe inhibitory potency of the compounds and raises the selectivity ofthe inhibition in respect of specific integrins. The selectivity can beinfluenced in particular by the N-alkyl groups.

The compounds can be employed as pharmaceutical active principles inhuman and veterinary medicine, in particular for the prophylaxis andtreatment of disorders of the circulation, thrombosis, cardiac infarct,arteriosclerosis, inflammations, apoplexy, angina pectoris, tumourdisorders, osteolytic disorders, especially osteoporosis, angiogenesisand disorders resulting from angiogenesis, for example diabeticretinopathy of the eye, ophthalmic diseases, macular degeneration,myopia, ocular histoplasmosis, rheumatic arthritis, osteoarthritis,rubeotic glaucoma, and also ulcerative colitis, Crohn's disease,multiple sclerosis, psoriasis and restenosis following angioplasty. Thecompounds may additionally be used to improve and support wound healingprocesses in the case of microbial infections and in acute renalfailure.

These actions can be demonstrated, for example, with the aid of methodsknown from the literature, as described for example by P. C. Brooks etal. in Cell. 79, 1157-1164 (1994) or Science 264, 569-571 (1994).

The abbreviations of amino acid residues shown above and below representthe residues of the following amino acids:

    ______________________________________                                        Abu          4-aminobutyric acid                                              Acha         α-aminocyclohexanecarboxylic acid                          AcpA         α-aminocyclopentanecarboxylic acid                         Aha          6-aminohexanoic acid                                             Ahds         16-aminohexadecanoic acid                                        Aib          3-aminoisobutyric acid                                           Ala          alanine                                                          Aos          8-aminooctanoic acid                                             Asn          asparagine                                                       Asp          aspartic acid                                                    Asp (OR)     aspartic acid (β ester)                                     Arg          arginine                                                         N-Ac-Arg     N-guanidinoacylarginine                                          Cha          3-cyclohexylalanine                                              Dab          2,4-diaminobutyric acid                                          Dap          2,3-diaminopropionic acid                                        Deg          diethylglycine                                                   Gln          glutamine                                                        Glu          glutamic acid                                                    Gly          glycine                                                          hPro         pipecolic acid                                                   His          histidine                                                        Ile          isoleucine                                                       Leu          leucine                                                          Lys          lysine                                                           Nal          3-(2-naphthyl) alanine                                           Nhdg         N-hexadecylglycine                                               Nle          norleucine                                                       Phe          phenylalanine                                                    homoPhe      homophenylalanine                                                4-Hal-Phe    4-halophenylalanine                                              Phg          phenylglycine                                                    Pro          proline                                                          Sar          sarcosine (N-methylglycine)                                      Tia          3-(2-thienyl) alanine                                            Tic          tetrahydroisoquinoline-3-carboxylic acid                         Thr          threonine                                                        Tle          tert-leucine (C.sub.α -tert-butylglycine)                  Trp          tryptophan                                                       Tyr          tyrosine                                                         Val          valine.                                                          ______________________________________                                    

In addition, the meaning of the following abbreviations is as follows:

    ______________________________________                                        BOC         tert-butoxycarbonyl                                               Bzl         benzyl                                                            DCCI        dicyclohexylcarbodiimide                                          DMF         dimethylformamide                                                 EDCI        N-ethyl-N'-(3-dimethylaminopropyl)-                                           carbodiimide × HCl                                          Et          ethyl                                                             Fmoc        9-fluorenylmethoxycarbonyl                                        HOBt        1-hydroxybenzotriazole                                            Me          methyl                                                            Mtr         4-methoxy-2,3,6-trimethylphenylsulfonyl                           NMe         N-methylated α-amino group                                  OBut        tert-butyl ester                                                  OMe         methyl ester                                                      OEt         ethyl ester                                                       POA         phenoxyacetyl                                                     TBTU        2-(1H-benzotriazol-1-yl)-1,1,3,3-                                             tetramethyluronium tetrafluoroborate                              TFA         trifluoroacetic acid.                                             ______________________________________                                    

Where the abovementioned amino acids can occur in a number ofenantiomeric forms, then all of these forms and also their mixtures(e.g. the DL forms) are included above and below, for example asconstituents of the compounds of the formula I. The amino acids, forexample as a constituent of compounds to the formula I, can also beprovided with appropriate protecting groups which are known per se.

In addition, the invention also includes those peptides whose amino acidresidues are fully or partially derivatized. The term "derivatized" isto be understood such that so-called "prodrugs", for exampleN-guanidino-acylderivatives of Arg, β-esters of Asp, Nε-alkanoyl,Nε-aminoalkanoyl and Nε-mercaptoalkanoyl derivatives of lysine, to namebut a few, are also included. In addition, the amino acid residues canin part be C-alpha-alkylated or, for example for diagnostic purposes,can be isotope-labelled. Also included are those compounds of theformula I which in the side chains of the units X and Y are additionallyderivatized by amino, carboxyl or mercapto groups, since suchderivatives are important starting compounds for the preparation ofconjugates of higher molecular weight, for example for immunizationpurposes and antibody production. It is additionally possible to usefunctional groups in the side chain of certain amino acid residues or ofderivatized amino acid residues to immobilize the peptides on polymermaterials for the production of affinity chromatography columns, or toutilize the functional groups for derivatization with diagnosticauxiliary reagents, such as fluorescent substituents.

The invention additionally relates to a process for the preparation of acompound of the formula I according to claim 1 or one of its salts,characterized in that it is liberated from one of its functionalderivatives by treatment with a solvolysing or hydrogenolysing agent orin that a peptide of the formula II

    H--Z--OH                                                   II

in which

Z is -Arg-Gly-Asp-X-Y-

-Gly-Asp-X-Y-Arg-

-Asp-X-Y-Arg-Gly-

-X-Y-Arg-Gly-Asp- or

-Y-Arg-Gly-Asp-X-,

or a reactive derivative of such a peptide, is treated with a cyclizingagent,

or in that a cyclopeptide which corresponds per se to the formula I butwhich has one or more free amino groups, acid groups and/or activated αcarbon atoms is derivatized by alkylation, acylation or esterification.

and/or in that a basic or acidic compound of the formula I is convertedinto one of its salts by treatment with an acid or base.

Above and below, the radicals X and Y have the meanings given in thecase of the formulae I and II unless expressly stated otherwise. Theletters used for the respective radicals have nothing to do with thesingle-letter code for amino acids.

In the above formulae, alkyl is preferably methyl, ethyl, isopropyl,n-butyl, sec-butyl or tert-butyl. However, alkyl is furthermore alsopreferably n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, n-decyl or n-hexadecyl.

The group X is preferably Phe, also preferably D-Phe, but alsoPhe(4-Hal), especially Phe(4-F) or Phe(4-Cl) and, homo-Phe or Phg, the Dforms also being equally preferred.

Y is preferably a hydrophobic amino acid residue, especially Gly, Ala,Val, Leu, Nle or Ile.

Accordingly, the invention relates in particular to those compounds ofthe formula I in which at least one of the radicals mentioned has one ofthe abovementioned preferred meanings.

A preferred group of compounds can be expressed by the subformula Ia,which otherwise corresponds to the formula I but in which

X is D-Phe, Phe, D-homoPhe, homophe, D-Phg, Phg, Phe(4-F), D-Phe(4-F),D-Phe(4-Cl) or Phe(4-Cl), and

Y is Nle, hpro, Ahds, Aos, Nhdg, Acha, Aib, Acpa, Tle, Ala, Leu or Ile,D and L froms being equally preferred.

Another preferred group of compounds can be expressed by the subformulaIb, which otherwise corresponds to the formula I but in which

X is D-Phe or Phe and

Y is Ahds, hpro, Aos, Nhdg, Acha, Aib, Acpa or Tle, D and L forms beingequally preferred,

and all the amino acid residues Arg, Gly or Asp are present in thenatural L configuration.

A further preferred group of compounds can be expressed by thesubformula Ic, which corresponds to the subformulae Ia and Ib and to theformula I but in which only one of the amino acid residues X or Y ispresent in the D form, whereas all the others are in the Lconfiguration.

Furthermore, particular preference is given to all physiologicallycompatible salts of the compounds which come under the subformulae Ia,Ib and Ic.

The compounds of the formula I and also the starting materials for theirpreparation are, moreover, prepared by known methods, as are describedin the literature (for example in the standard works such asHouben-Weyl, Methoden der organischen Chemie [Methods of organicChemistry], Georg-Thieme-Verlag, Stuttgart), in particular underreaction conditions which are known and appropriate for the saidreactions. In this context, use can also be made of known variants whichare not mentioned in any greater detail here.

If desired, the starting substances can also be formed in situ, so thatthey are not isolated from the reaction mixture but are immediatelyreacted further to give the compounds of the formula I.

The compounds of the formula I can be obtained by liberating them fromtheir functional derivatives by solvolysis, in particular hydrolysis, orby hydrogenolysis.

Preferred starting materials for the solvolysis or hydrogenolysis arethose which contain appropriate protected amino and/or hydroxyl groupsinstead of one or more free amino and/or hydroxyl groups, preferablythose which carry an amino protecting group instead of a hydrogen atomwhich is attached to a nitrogen atom, examples being those whichcorrespond to the formula I but which, instead of an NH₂ group, containan NHR' group (where R' is an amino protecting group, e.g. BOC or CBZ).

Other preferred starting materials are those which carry a hydroxylprotecting group instead of the hydrogen atom of a hydroxyl group, forexample those which correspond to the formula I but contain, instead ofa hydroxyphenyl group, a R" O-phenyl group (where R" is a hydroxylprotecting group).

It is also possible for two or more--identical or different--protectedamino and/or hydroxyl groups to be present in the molecule of thestarting material. If the protecting groups present are different fromone another, then in many cases they can be eliminated selectively.

The expression "amino protecting group" is generally known and relatesto groups which are suitable for protecting (for blocking) an aminogroup from chemical reactions but which are readily removable after thedesired chemical reaction has been carried out at other positions of themolecule. Typical of such groups are, in particular, unsubstituted orsubstituted acyl, aryl, aralkoxymethyl or arakyl groups. Since the aminoprotecting groups are removed after the desired reaction (or reactionsequence), their nature and size is otherwise not critical; however,preference is given to those having 1-20, in particular 1-8, carbonatoms. The term "acyl group" is to be interpreted in its widest sense inconnection with the present process. It includes acyl groups derivedfrom aliphatic, araliphatic, aromatic or heterocyclic carboxylic acidsor sulfonic acids and, in particular, alkoxycarbonyl, aryloxycarbonyland, above all, aralkoxycarbonyl groups. Examples of such acyl groupsare alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such asphenylacetyl; aroyl such as benzoyl or toluoyl; aryloxyalkanoyl such asPOA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl,2,2,2-trichlorethoxycarbonyl, BOC, 2-iodoethoxycarbonyl;aralkyloxycarbonyl such as CBZ ("carbobenzoxy"),4-methoxybenzyloxycarbonyl, FMOC; and arylsulfonyl such as Mtr.Preferred amino protecting groups are BOC and Mtr, and also CBZ, Fmoc,benzyl and acetyl.

The expression "hydroxyl protecting group" is also generally known andrelates to groups which are suitable for protecting a hydroxyl groupfrom chemical reactions but which are readily removable after thedesired chemical reaction has been carried out at other positions of themolecule. Typical of such groups are the abovementioned unsubstituted orsubstituted aryl, aralkyl or acyl groups, and also alkyl groups. Thenature and size of the hydroxyl protecting groups is not critical, sincethey are removed again after the desired chemical reaction or reactionsequence; preference is given to groups having 1-20, especially 1-10,carbon atoms. Examples of hydroxyl protecting groups include benzyl,p-nitrobenzoyl, p-toluenesulfonly, tert-butyl and acetyl, withparticular preference being given to benzyl and tert-butyl. The COOHgroups in aspartic acid and glutamic acid are preferably protected inthe form of their tert-butyl esters (e.g. Asp(OBut)).

The functional derivatives of the compounds of the formula I which areto be used as starting materials can be prepared by customary methods ofamino acid and peptide synthesis, as are described, for example, in thepatent applications and standard works mentioned, including for exampleby the solid-phase method according to Merrifield (B. F. Gysin and R. B.Merrifield, J. Am. Chem. Soc. 94, 3102 ff. (1972)).

The liberation of the compounds of the formula I from their functionalderivatives is carried out--depending on the protecting groupused--with, for example, strong acids, expediently with TFA orperchloric acid, but also with other strong inorganic acids, such ashydrochloric acid or sulfuric acid, strong organic carboxylic acids,such as trichloroacetic acid, or sulfonic acids such as benzene- orp-toluenesulfonic acid. The presence of an additional inert solvent ispossible but not always necessary. Suitable inert solvents arepreferably organic, for example carboxylic, acids such as acetic acid,ether such as tetrahydrofuran or dioxane, amides such as DMF,halogenated hydrocarbons such as dichloromethane, and also alcohols suchas methanol, ethanol or isopropanol, and water. Also suitable aremixtures of the abovementioned solvents. TFA is preferably used inexcess without the addition of a further solvent, perchloric acid in theform of a mixture of acetic acid and 70% perchloric acid in a ratio of9:1. The reaction temperatures for the cleavage are expediently betweenabout 0 and about 50°; it is preferably carried out between 15 and 30°(room temperature).

The groups BOC, OBut and Mtr can be removed, for example, preferablyusing TFA in dichloromethane or with about 3 to 5 N HCl in dioxane at15-30°, while the FMOC group can be eliminated with an approximately 5to 50% solution of dimethylamine, diethylamine or piperidine in DMF at15-30°.

Protecting groups which can be removed by hydrogenolysis (e.g. CBZ orbenzyl) can be eliminated, for example, by treatment with hydrogen inthe presence of a catalyst (e.g. a noble metal catalyst such aspalladium, preferably on a support such as charcoal). Suitable solventsin this context are those mentioned above, especially, for example,alcohols such as methanol or ethanol or amides such as DMF. Thehydrogenolysis is carried out, as a rule, at temperatures between about0 and 100° and at pressures of between about 1 and 200 bar, preferablyat 20-30° and 1-10 bar. Hydrogenolysis of the CBZ group, for example,takes place readily on 5 to 10% Pd-C in methanol or using ammoniumformate (instead of H₂) on Pd-C in methanol/DMF at 20-30°.

Compounds of the formula I can also be obtained by cyclization ofcompounds of the formula II under the conditions of a peptide synthesis.In this case, the reaction is expediently carried out in accordance withcustomary methods of peptide synthesis as described, for example, inHouben-Weyl, 1.c., Volume 15/II, Pages 1 to 806 (1974).

The reaction is preferably carried out in the presence of a dehydratingagent, for example a carbodiimide such as DCCI or EDCI, and additionallypropanephosphonic anhydride (cf. Angew. Chem. 92, 129 (1980)), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, inan inert solvent, for example a halogenated hydrocarbon such asdichloromethane, an ether such as tetrahydrofuran or dioxane, an amidesuch as DMF or dimethylacetamide, a nitrile such as acetonitrile, or inmixtures of these solvents, at temperatures between about -10 and 40,preferably between 0 and 30°. In order to promote intramolecularcyclization over intermolecular peptide bonding, it is expedient to workin dilute solutions (dilution principle).

Instead of II, suitable reactive derivatives of these substances canalso be employed in the reaction, for example those in which reactivegroups are intermediately blocked by protecting groups. The amino acidderivatives II can be used, for example, in the form of their activatedesters which are expediently formed in situ, for example by addition ofHOBt or N-hydroxysuccinimide.

In general, the starting materials of the formula II are novel. They canbe prepared by known methods, for example the abovementioned methods ofpeptide synthesis and of elimination of protecting groups.

In general, protected pentapeptide esters of the formula R'--Z--OR", forexample BOC-Z-OMe or BOC-Z-OEt, are initially synthesized, which arefirst of all hydrolized to give acids of the formula R'--Z--OH, forexample BOC-Z--OH; the protecting group R' is eliminated from theseacids to give the free peptides of the formula H--Z--OH (II).

The derivatization of a cyclopeptide which corresponds per se to acompound of the formula I is likewise effected by methods known per se,as are known for the alkylation of amines, the esterification ofcarboxylic acids or nucleophilic substitution at aliphatic carbon atomsand are described in any textbook of organic chemistry, for example J.March, Adv. Org. Chem., John Wiley & Sons N.Y. (1985).

A base of the formula I can be converted into the associated acidaddition salt using an acid. Suitable acids for this reaction are, inparticular, those which yield physiologically acceptable salts. Thusinorganic acids can be used, examples being sulfuric acid, nitric acid,hydrohalic acids such as hydrochloric acid or hydrobromic acid,phosphoric acid such as orthophosphoric acid, sulfamic acid, and alsoorganic acids, especially aliphatic, alicyclic, araliphatic, aromatic orheterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids,for example formic acid, acetic acid, propionic acid, pivalic acid,diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaricacid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid,salicylic acid, 2- or 3-phenylpropionic acid, citric acid, gluconicacid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- orethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono-and -disulfonic acids, laurylsulfuric acid. Salts with physiologicallyunacceptable acids, for example picrates, can be used for isolatingand/or purifying the compounds of the formula I.

Alternatively, an acid of the formula I can be converted into one of itsphysiologically acceptable metal or ammonium salts by reaction with abase. Particularly suitable salts in this context are the sodium,potassium, magnesium, calcium and ammonium salts, and also substitutedammonium salts, for example the dimethyl-, diethyl- ordiisopropylammonium salts, monoethanol-, diethanol- ortriethanolammonium salts, cyclohexylammonium salts, dicyclohexylammoniumsalts, dibenzylethylenediammonium salts, and also, for example, saltswith N-methyl-D-glucamine or with arginine or lysine.

The novel compounds of the formula I and their physiologicallyacceptable salts can be used for the production of pharmaceuticalpreparations by bringing them into a suitable dosage form together withat least one excipient or auxiliary and, if desired, together with oneor more other active principles. The preparations thus obtained can beemployed as medicaments in human or veterinary medicine. Suitableexcipient substances are organic or inorganic substances which aresuitable for enteral (e.g. oral or rectal), parenteral (e.g. intrevenousinjection) or local (e.g. topical, dermal, ophthalmic or nasal)administration or for administration in the form of an inhalation sprayand which do not react with the novel compounds, examples being water oraqueous isotonic saline solution, lower alcohols, vegetable oils, benzylalcohols, polyethylene glycols, glycerol triacetate and other fatty acidglycerides, gelatine, soya lecithin, carbohydrates such as lactose orstarch, magnesium stearate, talc, cellulose and petroleum jelly. Fororal application, plain tablets, coated tablets, capsules, syrups,juices or drops are particularly useful; coated tablets and capsuleshaving enteric coatings or capsule shells are especially of interest.Suppositories are used for rectal administration, solutions forparenteral administration, preferably oily or aqueous solutions, andalso suspensions, emulsions or implants. Examples of forms suitable fortopical application are solutions, which can be used in the form of eyedrops, and also, for example, suspensions, emulsions, creams, ointmentsor compresses. For administration in the form of an inhalation spray itis possible to use sprays which contain the active principle eitherdissolved or suspended in a propellant gas or propellant gas mixture(e.g. CO₂ or fluorochlorohydrocarbon substitutes). In this case theactive principle is expediently used in micronized form, with thepresence of one or more additional, physiologically compatible solvents,such as ethanol, being possible. Inhalation solutions can beadministered with the aid of customary inhalers. The novel compounds canalso be lyophilized and the resulting lypholisates used, for example,for producing injection preparations. The injections can be given as abolus or in the form of a continuous infusion (for example intravenous,intramuscular, subcutaneous or intrathecal). The preparations stated canbe sterilized and/or can comprise auxiliaries such as preservatives,stabilizers and/or wetting agents, emulsifiers, salts for influencingthe osmotic pressure, buffer substances, colourants and/or flavourings.If desired they can also contain one or more other active ingredients,including for example one or more vitamins.

In general, the substances according to the invention can beadministered in analogy to other known, commercially available peptides,but in particular in analogy to the compounds described in U.S. Pat. No.4,472,305, preferably in dosages of between about 0.05 and 500 mg, inparticular between 0.5 and 100 mg, per dosage unit. The daily dose ispreferably between about 0.01 and 2 mg/kg of body weight. The specificdose for each particular patient depends, however, on a wide variety offactors, for example, the activity of the specific compound employed,the age, body weight, general condition of health, gender, the diet,time and route of administration, rate of excretion, combination ofmedicaments and severity of the particular disease to which the therapyis applied. Parenteral administration is preferred.

Furthermore, the novel compounds of the formula I can be used asintegrin ligands for the production of columns for affinitychromatography for the preparation of integrins in pure form.

In this case, the ligand, i.e. a peptide derivative of the formula I, iscovalently coupled to a polymeric support via anchor functions.

Suitable polymeric support materials are the polymeric solid faces knownin peptide chemistry, preferably having hydrophilic properties, forexample crosslinked polysugars, such as cellulose, Sepharose orSephadex®, acrylamides, polymers based on polyethylene glycol orTentakel® polymers.

Suitable anchor functions which are linked to the polymeric supports arepreferably linear alkylene chains having 2-12 carbon atoms, which arebonded directly to the polymer at one end and have a functional group,for example hydroxyl, amino, mercapto, maleimido or --COOH at the otherend and are suitable for linking to the C- or N-terminal section of therespective peptide.

In this case it is possible for the peptide to be bonded directly orlikewise via a second anchor function to the anchor of the polymer. Itis also possible for peptides containing amino acid residues havingfunctionalized side chains to be attached via these chains to the anchorfunction of the polymer.

Furthermore, certain amino acid residues, which are a constituent of thepeptides of the formula I, can be modified in their side chains suchthat they are available for anchorage via, for example, SH, OH, NH₂ orCOOH groups with the anchor of the polymer.

In this connection, unusual amino acids are possible, examples beingphenylalanine derivatives which in position 4 of the phenyl ring carry amercapto, hydroxyl, amino or carboxyalkyl chain, the functional groupbeing located at the end of the chain.

Examples of amino acid residues whose side chain can be used directly asan anchor function are e.g. Lys, Arg, Asp, Asn, Glu, Gln, Ser, Thr, Cysor Tyr.

Examples of N-terminal anchors are radicals such as e.g. --CO--C_(n)H_(2n) --NH₂, --CO--C_(n) H_(2n) --OH, --CO--C_(n) H_(2n) --SH or--CO--C_(n) H_(2n) --COOH where n=2-12, the length of the alkylene chainnot being critical and it also being possible, if desired, for thischain to be replaced by appropriate aryl or alkylaryl radicals, forexample.

C-terminal anchors can be, for example, --O--C_(n) H_(2n) --SH--,--O--C_(n) H_(2n) --OH, --O--C_(n) H_(2n) --NH₂, --O--C_(n) H_(2n)--COOH, --NH--C_(n) H_(2n) --SH, --NH--C_(n) H_(2n) --OH, --NH--C_(n)H_(2n) --NH₂ or --NH--C_(n) H_(2n) --COO, both n and the alkylene chainbeing subject to the comments already made in the preceding section.

The N- and C-terminal anchors can also be used as anchor component foran already functionalized side chain of an amino acid residue. Suitableamino acid residues in this case are those such as Lys(CO--C₅ H₁₀--NH₂), Asp (NH--C₃ H₆ --COOH) or Cys (C₃ H₆ --NH₂), the anchor alwaysbeing attached to the functional group of the side chain.

The materials for affinity chromatography for purifying integrins areprepared under conditions such as are customary for the condensation ofamino acids and are known per se, and have already been outlined in thesection for the preparation of the compounds of the formula I.

In addition to the use of cyclopeptides for immobilization on polymermaterials for the production of affinity chromatography columns it ispossible to utilize the compounds with their functionalized side chainsfor further derivatization with diagnostic auxiliary reagents, forexample fluorescent substituents.

It is also possible to introduce, in addition, functional groups such asamino, mercapto or carboxyl groups into the side chains of the radicalsD and E, by way of which groups it is then possible to prepareconjugates with proteins or other high molecular mass substances, forexample for immunization purposes and/or antibody production.

All temperatures stated above and below are in ° C. In the examplesbelow, "customary working up" means: water is added if necessary, themixture is neutralized and subjected to extraction with ether ordichloromethane, the phases are separated, the organic phase is driedover sodium sulfate, filtered and concentrated by evaporation and theresidue is purified by chromatography on silica gel and/orcrystallization. RT=retention time (minutes). Analysis was by HPLC onLichrosorb® RP select B (7 μm)-250×4 mm column, Eluent A: 0.3% TFA inwater; Eluent B: 0.3% TFA in 2-propanol/water (8:2) gradient 1-99% B in50 minutes at 1 ml/min flow rate and detection at 215 nm. M+=molecularpeak in the mass spectrum obtained by the "Fast Atom Bombardment" (FAB)method.

EXAMPLE 1

A solution of 1.1 g of H-Arg(Mtr)-Gly-Asp(OBut)-D-Phe-hPro-ONa[obtainable, for example, fromFmoc-NMe-Arg(Mtr)-Gly-Asp(OBut)-D-Phe-hPro-O-Wang, --O-Wang being theradical of a 4-oxymethyl-phenoxymethyl-polystyrene resin used in themodified Merrifield techniques, by removal of the Fmoc group withpiperidine/DMF and elimination of the resin with TFA/CH₂ Cl₂ (1:1)] in15 ml of DMF is diluted with 85 ml of dichloromethane, and 50 mg ofNaHCO₃ are added. After cooling in a dry ice/acetone mixture, 40 μl ofdiphenylphosphoryl azide are added. After standing at room temperaturefor 16 hours, the solution is concentrated. The concentrate isgel-filtered (Sephadex G10 column in isopropanol/water 8:2) and thenpurified by HPLC in the customary manner. Treatment with TFA/H₂ O (98:2)gives cyclo-(Arg-Gly-Asp-D- Phe-hPro); RT=18.5; FAB-MS (M+H): 587.

The following are obtained analogously by cyclization of thecorresponding linear peptides and removal of the protecting groups:

cyclo-(Arg-Gly-Asp-DPhe-Nle); RT=25.3; FAB-MS(M+H): 589;

cyclo-(Arg-Gly-Asp-Phe-Ahds); RT=35.1; FAB-MS(M+H): 730;

cyclo-(Arg-Gly-Asp-DPhe-Ahds); RT=35.4; FAB-MS(M+H): 730;

cyclo-(Arg-Gly-Asp-Phe-DAhds); RT=35.7; FAB-MS(M+H): 730;

cyclo-(Arg-Gly-Asp-DPhe-Aos);

cyclo-(Arg-Gly-Asp-DPhe-DAos);

cyclo-(Arg-Gly-Asp-Phe-DAos);

cyclo-(Arg-Gly-Asp-DPhe-Nhdg); RT=36.7; FAB-MS(M+H): 758;

cyclo-(Arg-Gly-Asp-Phe-Nhdg); RT=36.5; FAB-MS(M+H): 758;

cyclo-(Arg-Gly-Asp-DPhe-DNhdg); FAB-MS(M+H): 758;

cyclo-(Arg-Gly-Asp-Phe-DNhdg); FAB-MS(M+H): 758;

cyclo-(Arg-Gly-Asp-DPhg-Nhdg);

cyclo-(Arg-Gly-Asp-Phg-Nhdg);

cyclo-(Arg-Gly-Asp-DPhg-DNhdg);

cyclo-(Arg-Gly-Asp-Phg-DNhdg);

cyclo-(Arg-Gly-Asp-DPhe-Acha); RT=25.2; FAB-MS(M+H): 601;

cyclo-(Arg-Gly-Asp-Phe-Acha); FAB-MS(M+H): 601;

cyclo-(Arg-Gly-Asp-DPhe-DAcha); FAB-MS(M+H): 601;

cyclo-(Arg-Gly-Asp-Phe-DAcha); FAB-MS(M+H): 601;

cyclo-(Arg-Gly-Asp-DPhe-Aib); FAB-MS(M+H): 575;

cyclo-(Arg-Gly-Asp-Phe-Aib); RT=36.5; FAB-MS(M+H):575;

cyclo-(Arg-Gly-Asp-DPhe-DAib); FAB-MS(M+H): 575;

cyclo-(Arg-Gly-Asp-Phe-DAib); FAB-MS(M+H): 575;

cyclo-(Arg-Gly-Asp-DPhe-Acpa); RT=17.1; FAB-MS(M+H): 587;

cyclo-(Arg-Gly-Asp-Phe-Acpa); FAB-MS(M+H): 587;

cyclo-(Arg-Gly-Asp-DPhe-DAcpa); FAB-MS(M+H): 587;

cyclo-(Arg-Gly-Asp-Phe-DAcpa); FAB-MS(M+H): 587;

cyclo-(Arg-Gly-Asp-DPhe-Tle); RT=19.1; FAB-MS(M+H): 589;

cyclo-(Arg-Gly-Asp-Phe-Tle); FAB-MS(M+H): 589;

cyclo-(Arg-Gly-Asp-DPhe-DTle); FAB-MS(M+H): 589;

cyclo-(Arg-Gly-Asp-Phe-DTle); FAB-MS(M+H): 589;

cyclo-(Arg-Gly-Asp-Dphe(4-Cl)-Tle); RT=23.2; FAB-MS(M+H): 623;

cyclo-(Arg-Gly-Asp-Phe(4-Cl)-Tle); FAB-MS(M+H): 623;

cyclo-(Arg-Gly-Asp-DPhe(4-Cl)-DTle); FAB-MS(M+H): 623;

cyclo-(Arg-Gly-Asp-Phe(4-Cl)-DTle); FAB-MS(M+H): 623;

cyclo-(Arg-Gly-Asp-Dphe(4-F)-Tle); RT=20.2; FAB-MS(M+H): 607;

cyclo-(Arg-Gly-Asp-Phe(4-F)-Tle); FAB-MS(M+H): 607;

cyclo-(Arg-Gly-Asp-DPhe(4-F)-DTle); FAB-MS(M+H): 607;

cyclo-(Arg-Gly-Asp-Phe(4-F)-DTle); FAB-MS(M+H): 607.

EXAMPLE 2

A solution of 0.28 g of cyclo-(Arg(Mtr)-Gly-Asp-DPhe-DhPro) [obtainableby cyclization according to Ex. 1] in 8.4 ml of TFA, 1.7 ml ofdichloromethane and 0.9 ml of thiophenol is allowed to stand at roomtemperature for 4 hours, then concentrated, and the residue is dilutedwith water and then freeze-dried. Gel filtration on Sephadex G 10(acetic acid/water 1:1) and subsequent purification by preparative HPLCunder the conditions indicated give cyclo-(Arg-Gly-Asp-DPhe-DhPro);FAB-MS (M+H): 587.

The following are obtained analogously:

from cyclo-(Arg(Mtr)-Gly-Asp-Phe-DhPro):

cyclo-(Arg-Gly-Asp-Phe-DhPro);

FAB-MS (M+H): 587;

from cyclo-(Arg(Mtr)-Gly-Asp(OBut)-DPhg-Tle):

cyclo-(D-Arg-NMeGly-Asp-DPhg-Tle);

from cyclo-(Arg(Mtr)-Gly-Asp(OEt)-DPhg-hPro):

cyclo-(Arg-Gly-Asp-DPhg-hPro);

from cyclo-(Arg(Mtr)-Gly-Asp-Phg-DAhds):

cyclo-(Arg-Gly-Asp-Phg-DAhds);

from cyclo-(Arg(Mtr)-Gly-Asp-DPhg-Acpa):

cyclo-(Arg-Gly-Asp-DPhg-Acpa);

from cyclo-(Arg(Mtr)-Gly-Asp-DPhg-Aos):

cyclo-(Arg-Gly-Asp-DPhg-Aos).

EXAMPLE 3

80 mg of cyclo-(Arg-Gly-Asp-DPhe-hPro) [obtainable according to Ex. 1]are dissolved in 0.01 m HCl five to six times and freeze-dried aftereach dissolving operation. Subsequent purification by HPLC givescyclo-(Arg-Gly-Asp-DPhe-hPro)×HCl.

The following are obtained analogously:

from cyclo-(Arg-Gly-Asp-DPhe-Nle):

cyclo-(Arg-Gly-Asp-DPhe-Nle):×HCl;

from cyclo-(Arg-Gly-Asp-DPhe-Ahds):

cyclo-(Arg-Gly-Asp-DPhe-Ahds)×HCl;

from cyclo-(Arg-Gly-Asp-DPhe-Ahds):

cyclo-(Arg-Gly-Asp-DPhe-Ahds)×HCl.

EXAMPLE 4

To prepare affinity phases, 0.9 g of N-maleimido-(CH₂)₅ --CO--NH--(CH₂)₃polymer [obtainable by condensation of N-maleimido-(CH₂)₅ --COOH with H₂N--(CH₂)₃ polymer] is suspended in 10 ml of 0.1 M sodium phosphatebuffer at a pH of 7, and one equivalent cyclo-(Arg-Gly-Asp-DPhe(4-N--CO(CH₂)₂ SH)-hPro) [obtainable by cyclization ofH-Dphe(4-NH-BOC)-hPro-Arg(Mtr)-Gly-Asp-OH, removal of the protectinggroups and acylation with, for example, Cl--CO(CH₂)₂ SH] is added at 4°.The reaction mixture is stirred for 4 hours with simultaneous warming toroom temperature, and the solid residue is filtered off and washed twicewith 10 ml each of buffer solution (pH 7) and then three times with 10ml each time of water. Cyclo-(Arg-Gly-Asp-DPhe (4-N--CO (CH₂)₂S--3-(N-maleimido-(CH₂)₅ --CONH--(CH₂)₃ -polymer)-hpro)) is obtained.

EXAMPLE 5

Analogously to Example 4, condensation of polymer-O--(CH₂)₃ --NH₂[commercially available] and cyclo-(Arg-Gly-Asp-DPhe (4-N--CO(CH₂)₄--COOH)=hpro) [obtainable by condensing adipic acid withcyclo-(Arg(Mtr)-Gly-Asp-DPhe-(4-NH-BOC)-hPro) under the conditionsstated in Ex. 4] gives the following polymeric phase:cyclo-(Arg-Gly-Asp-DPhe (4-N--CO--(CH₂)₄ --CO--NH--(CH₂)₃--O-polymer)-hPro).

The following examples relate to pharmaceutical preparations.

EXAMPLE A Injection Vials

A solution of 100 g of a cyclopeptide of the formula I and 5 g ofdisodium hydrogen phosphate in 3 l of double-distilled water is adjustedto a pH of 6.5 with 2 N hydrochloric acid, subjected to sterilefiltration, dispensed into injection vials and lyophilized under sterileconditions, and the vials are sealed in a sterile manner. Each injectionvial contains 5 mg of active principle.

EXAMPLE B Suppositories

A mixture of 20 g of active principle of the formula I is melted with100 g of soya lecithin and 1400 g of cocoa butter, and the mixture ispoured into moulds and allowed to cool. Each suppository contains 20 mgof active principle.

EXAMPLE C Solution

A solution is prepared from 1 g of active principle of the formula I,9.38 g of NaH₂ PO₄ ×2 H₂ O, 28.48 g of Na₂ HPO₄ ×12 H₂ O and 0.1 g ofbenzalkonium chloride in 940 ml of double-distilled water. The pH isadjusted to 6.8, the solution is made up to 1 l and is sterilized byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of active principle of the formula I are mixed with 99.5 g ofpetroleum jelly under aseptic conditions.

EXAMPLE E Tablets

A mixture of 100 g of a cyclopeptide of the formula I, 1 kg of lactose,600 g of microcrystalline cellulose, 600 g of maize starch, 100 g ofpolyvinylpyrrolidone, 80 g of talc and 10 g of magnesium stearate ispressed to give tablets in a customary manner, such that each tabletcontains 10 g [sic] of active principle.

EXAMPLE F Coated Tablets

Tablets are pressed as stated in Example E and are then coated in acustomary manner with a coating of sucrose, maize starch, talc,tragacanth and colourant.

EXAMPLE G Capsules

Hard gelatine capsules are filled in a customary manner with an activeprinciple of the formula I such that each capsule contains 5 mg ofactive principle.

EXAMPLE H Inhalation Spray

14 g of active principle of the formula I are dissolved in 10 l ofisotonic NaCl solution, and the solution is used to fill commerciallyavailable spray canisters having a pump mechanism. The solution can besprayed into the mouth or nose. One spray burst (about 0.1 ml)corresponds to a dose of about 0.14 mg.

    __________________________________________________________________________    #             SEQUENCE LISTING                                                - <160> NUMBER OF SEQ ID NOS: 9                                               - <210> SEQ ID NO 1                                                           <211> LENGTH: 5                                                               <212> TYPE: PRT                                                               <213> ORGANISM: Artificial Sequence                                           <220> FEATURE:                                                                #Sequence:R INFORMATION: Description of Artificial                                   cyclopeptide                                                           <220> FEATURE:                                                                <221> NAME/KEY: MOD.sub.-- RES                                                <222> LOCATION: (5)                                                           <223> OTHER INFORMATION: Ahds                                                 - <400> SEQUENCE: 1                                                           - Arg Gly Asp Phe Xaa                                                           1               5                                                           - <210> SEQ ID NO 2                                                           <211> LENGTH: 5                                                               <212> TYPE: PRT                                                               <213> ORGANISM: Artificial Sequence                                           <220> FEATURE:                                                                #Sequence:R INFORMATION: Description of Artificial                                  cyclopeptide                                                            <220> FEATURE:                                                                <221> NAME/KEY: MOD.sub.-- RES                                                <222> LOCATION: (5)                                                           <223> OTHER INFORMATION: Nhdg                                                 - <400> SEQUENCE: 2                                                           - Arg Gly Asp Phe Xaa                                                           1               5                                                           - <210> SEQ ID NO 3                                                           <211> LENGTH: 5                                                               <212> TYPE: PRT                                                               <213> ORGANISM: Artificial Sequence                                           <220> FEATURE:                                                                #Sequence:R INFORMATION: Description of Artificial                                  cyclopeptide                                                            <220> FEATURE:                                                                <221> NAME/KEY: MOD.sub.-- RES                                                <222> LOCATION: (4)                                                           <223> OTHER INFORMATION: Phg                                                  <220> FEATURE:                                                                <221> NAME/KEY: MOD.sub.-- RES                                                <222> LOCATION: (5)                                                           <223> OTHER INFORMATION: Nhdg                                                 - <400> SEQUENCE: 3                                                           - Arg Gly Asp Xaa Xaa                                                           1               5                                                           - <210> SEQ ID NO 4                                                           <211> LENGTH: 5                                                               <212> TYPE: PRT                                                               <213> ORGANISM: Artificial Sequence                                           <220> FEATURE:                                                                #Sequence:R INFORMATION: Description of Artificial                                  cyclopeptide                                                            <220> FEATURE:                                                                <221> NAME/KEY: MOD.sub.-- RES                                                <222> LOCATION: (5)                                                           <223> OTHER INFORMATION: Acha                                                 - <400> SEQUENCE: 4                                                           - Arg Gly Asp Phe Xaa                                                           1               5                                                           - <210> SEQ ID NO 5                                                           <211> LENGTH: 5                                                               <212> TYPE: PRT                                                               <213> ORGANISM: Artificial Sequence                                           <220> FEATURE:                                                                #Sequence:R INFORMATION: Description of Artificial                                  cyclopeptide                                                            <220> FEATURE:                                                                <221> NAME/KEY: MOD.sub.-- RES                                                <222> LOCATION: (5)                                                           <223> OTHER INFORMATION: Aib                                                  - <400> SEQUENCE: 5                                                           - Arg Gly Asp Phe Xaa                                                           1               5                                                           - <210> SEQ ID NO 6                                                           <211> LENGTH: 5                                                               <212> TYPE: PRT                                                               <213> ORGANISM: Artificial Sequence                                           <220> FEATURE:                                                                #Sequence:R INFORMATION: Description of Artificial                                  cyclopeptide                                                            <220> FEATURE:                                                                <221> NAME/KEY: MOD.sub.-- RES                                                <222> LOCATION: (5)                                                           <223> OTHER INFORMATION: Acpa                                                 - <400> SEQUENCE: 6                                                           - Arg Gly Asp Phe Xaa                                                           1               5                                                           - <210> SEQ ID NO 7                                                           <211> LENGTH: 5                                                               <212> TYPE: PRT                                                               <213> ORGANISM: Artificial Sequence                                           <220> FEATURE:                                                                #Sequence:R INFORMATION: Description of Artificial                                  cyclopeptide                                                            <220> FEATURE:                                                                <221> NAME/KEY: MOD.sub.-- RES                                                <222> LOCATION: (5)                                                           <223> OTHER INFORMATION: Tle                                                  - <400> SEQUENCE: 7                                                           - Arg Gly Asp Phe Xaa                                                           1               5                                                           - <210> SEQ ID NO 8                                                           <211> LENGTH: 5                                                               <212> TYPE: PRT                                                               <213> ORGANISM: Artificial Sequence                                           <220> FEATURE:                                                                #Sequence:R INFORMATION: Description of Artificial                                  cyclopeptide                                                            <220> FEATURE:                                                                <221> NAME/KEY: MOD.sub.-- RES                                                <222> LOCATION: (4)                                                           <223> OTHER INFORMATION: Phe (4-Cl)                                           <220> FEATURE:                                                                <221> NAME/KEY: MOD.sub.-- RES                                                <222> LOCATION: (5)                                                           <223> OTHER INFORMATION: Tle                                                  - <400> SEQUENCE: 8                                                           - Arg Gly Asp Phe Xaa                                                           1               5                                                           - <210> SEQ ID NO 9                                                           <211> LENGTH: 5                                                               <212> TYPE: PRT                                                               <213> ORGANISM: Artificial Sequence                                           <220> FEATURE:                                                                #Sequence:R INFORMATION: Description of Artificial                                  cyclopeptide                                                            <220> FEATURE:                                                                <221> NAME/KEY: MOD.sub.-- RES                                                <222> LOCATION: (4)                                                           <223> OTHER INFORMATION: Phe (4-F)                                            <220> FEATURE:                                                                <221> NAME/KEY: MOD.sub.-- RES                                                <222> LOCATION: (5)                                                           <223> OTHER INFORMATION: Tle                                                  - <400> SEQUENCE: 9                                                           - Arg Gly Asp Phe Xaa                                                           1               5                                                           __________________________________________________________________________

What is claimed is:
 1. A cyclopeptide of formula I

    cyclo-(Arg-Gly-Asp-X-Y)                                    I,

and the physiologically acceptable salts thereof, wherein X is Phe,homoPhe, Phg, Phe(4-F) or Phe(4-Cl), Y is hPro, Ahds, Aos, Nhdg, Acha,Aib, Acpa or Tle,wherein, when X and Y represent optically active aminoacid residues, both the D and L forms are included, wherein Argrepresents arginine or N-guanidine-acyl derivatives of arginine, andwherein Asp represents aspartic acid and β-esters of aspartic acid. 2.An enantiomer or a diastereomer of a compound of the formula I accordingto claim
 1. 3. (a) Cyclo-(Arg-Gly-Asp-DPhe-hPro);(b)Cyclo-(Arg-Gly-Asp-DPhe-Tle); (c) Cyclo-(Arg-Gly-Asp-Phe-DAhds); (d)Cyclo-(Arg-Gly-Asp-Phe-Nhdg); (e) Cyclo-(Arg-Gly-Asp-DPhe-Acha); (f)Cyclo-(Arg-Gly-Asp-Dphe (4-Cl)-Tle); (g) Cyclo-(Arg-Gly-Asp-Dphe(4-F)-Tle); according to claim 1 and also their physiologicallyacceptable salts.
 4. A composition comprising at least one compound ofthe general formula I according to claim 1 and a pharmaceuticallyacceptable carrier.
 5. A composition comprising at least one compound ofthe general formula I according to claim 1 and a carrier.